This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
PCT/EP96/00368 (WO-A-96/23783, 08.08.96) (SmithKline Beecham plc) describes indole and indoline derivatives which are described as possessing 5HT2C/2B receptor antagonist activity. A novel class of compounds has now been discovered which fall within the generic scope of PCT/EP96/00368, but are not specifically disclosed therein, and have been found to exhibit a surprisingly enhanced 5HT2C receptor antagonist activity profile (enhanced activity and duration of action after oral dosing). 5HT2C receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome) as well as microvascular diseases such as macular oedema and retinopathy.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof: 
wherein:
X is CH or N;
R1 is hydrogen or C1-6 alkyl;
R2 and R3 groups are independently C1-6 alkyl or trifluoromethyl.
C1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Preferably X is CH.
Preferably R1 is methyl.
Preferably R2 is CF3 (trifluoromethyl).
Preferably R3 is C1-6 alkyl, particularly methyl.
Particular compounds of the invention include: 5-Methyl-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)-pyridin-3-ylcarbamoyl]indoline. This compound can also be named as 5-Methyl-1-[2-(2-methylpyridin-3-yloxy)-5-pyridylcarbamoyl]-6-trifluoromethylindoline or 2,3-Dihydro-5-methyl-N-[2-(2-methyl-3-pyridinyl)oxy]-5-pyridinyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide, 5-Methyl-1-[6-(2-methylpyridin-3-yloxy)-pyridazin-3-ylcarbamoyl]-6-trifluoromethylindoline, and pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic acids. A particularly preferred salt is 5-Methyl-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)-pyridin-3-ylcarbamoyl]indoline monohydrochloride.
Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms. The invention also extends to any tautomeric forms of the compounds of formula (I) and mixtures thereof. When referred to herein, it is understood that the term xe2x80x98compound of formula (I)xe2x80x99 also includes all these forms. The compounds of the invention can be prepared using standard procedures such as those of PCT/EP96/00368 (WO-A-96/23783), for example by the coupling of a compound of formula (II); 
with a compound of formula (III); 
in which R1, R2 and R3 are as defined in formula (I) and A and B contain the appropriate functional group(s) necessary to form the moiety xe2x80x94NHCOxe2x80x94 when coupled and thereafter optionally forming a pharmaceutically acceptable salt thereof Suitable examples of groups A and B include:
(i) A is xe2x80x94Nxe2x95x90Cxe2x95x90O and B is hydrogen,
(ii) A is xe2x80x94NHCOL and B is hydrogen,
(iii) A is xe2x80x94NH2 and B is COL, or
(iv) A is halogen and B is xe2x80x94CONH2 wherein L is a leaving group. Examples of suitable leaving groups L include halogen such as chloro or bromo, imidazole, or phenoxy or phenylthio optionally substituted, for example, with halogen.
Preferably A is xe2x80x94NHCOL and B is hydrogen; particularly preferably A is xe2x80x94NHCOOPh and B is hydrogen.
Compounds of formula (II) and (III) may be prepared according to known methods or analogous to known methods and to methods described in the following descriptions, for example using the procedures described in WO 95/01976 and PCT/EP96/00368 (WO-A-96/23783).
Novel intermediates of formula (II) also form part of the invention.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2C receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders (including disturbances of Circadian rhythm), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.